Hoover-Plow J L, Miles L A, Fless G M, Scanu A M, Plow E F
Committee on Vascular Biology (CVB-1), Scripps Research Institute, La Jolla, California 92037.
Biochemistry. 1993 Dec 14;32(49):13681-7. doi: 10.1021/bi00212a037.
Regions of apoprotein(a) of lipoprotein(a) [Lp(a)] exhibit striking primary sequence homology to the kringles of plasminogen. The kringles of plasminogen are lysine binding structures and mediate interactions of plasmin(ogen) with substrates and inhibitors. In the current study, the lysine binding properties of Lp(a) have been compared to those of plasminogen and isolated kringle 4 of plasminogen (K4). An analytical assay was implemented to quantitate the interaction of kringle-containing molecules with lysine-Sepharose beads. Radioiodinated ligands, Lp(a), plasminogen, and K4, bound to the beads, and their interactions were inhibited by lysine analogues in a dose-dependent fashion. A series of omega-aminocarboxylic acids inhibited Lp(a), plasminogen, and K4 binding to the lysine-Sepharose beads, but marked differences in the effectiveness of these compounds were observed with each ligand. In this series of compounds, 6-aminohexanoic acid was the most potent inhibitor of binding to lysine-Sepharose for all three ligands. The pH had little effect on the inhibition of plasminogen binding by these compounds. For Lp(a), a low pH caused a marked decrease in inhibition by the 5-carbon and 4-carbon omega-amino acids. In addition, tranexamic acid was 750-fold more potent than lysine in inhibiting plasminogen and 55-fold more potent for K4 binding to the beads. In contrast, the differential potency of these compounds on Lp(a) binding was only 3-fold. These results suggest that the kringles of Lp(a) possess lysine binding functions which are similar, but not identical, to those of plasminogen and its K4.(ABSTRACT TRUNCATED AT 250 WORDS)
脂蛋白(a)[Lp(a)]的载脂蛋白(a)区域与纤溶酶原的kringle结构域具有显著的一级序列同源性。纤溶酶原的kringle结构域是赖氨酸结合结构，介导纤溶酶(原)与底物及抑制剂的相互作用。在本研究中，已将Lp(a)的赖氨酸结合特性与纤溶酶原及纤溶酶原的分离kringle 4(K4)的特性进行了比较。采用一种分析测定法来定量含kringle分子与赖氨酸-琼脂糖珠的相互作用。放射性碘标记的配体Lp(a)、纤溶酶原和K4与珠子结合，它们的相互作用被赖氨酸类似物以剂量依赖方式抑制。一系列ω-氨基羧酸抑制Lp(a)、纤溶酶原和K4与赖氨酸-琼脂糖珠的结合，但观察到这些化合物对每种配体的有效性存在显著差异。在这一系列化合物中，6-氨基己酸是所有三种配体与赖氨酸-琼脂糖结合的最有效抑制剂。pH对这些化合物抑制纤溶酶原结合的影响很小。对于Lp(a)，低pH导致5碳和4碳ω-氨基酸的抑制作用显著降低。此外，氨甲环酸在抑制纤溶酶原方面比赖氨酸强750倍，在抑制K4与珠子结合方面比赖氨酸强55倍。相比之下，这些化合物对Lp(a)结合的效力差异仅为3倍。这些结果表明，Lp(a)的kringle结构域具有与纤溶酶原及其K4相似但不完全相同的赖氨酸结合功能。(摘要截短于250字)
